The Interferon-beta (IFN-beta)/SETDB2 Epigenetic Axis Regulates Inflammation And Metabolism In Diabetic Wounds

项目摘要/摘要 2型糖尿病(T2D)患者的不可愈合伤口是发病率和死亡率的主要原因 正以惊人的速度增长。巨噬细胞功能的控制因素及这些细胞如何转化 伤口组织中从炎症到修复的表型尚不清楚；在 我们预防和治疗这些伤口的能力。我们的实验室正在研究新的表观遗传学变化， 通过组蛋白的过渡后修饰，作为调节巨噬细胞表型的机制(S) 伤口愈合。我们提供的数据表明，创伤后建立的细胞因子环境会导致 巨噬细胞中控制基因转录的特定表观遗传机制的表达，因此， 功能。使用人类细胞和我们的创伤愈合实验小鼠模型，我们已经确定 干扰素β诱导SETDB2的表达，这是一种基于表观遗传学的赖氨酸甲基转移酶 负责设置抑制性组蛋白标记，导致炎症和代谢沉默 基因。这一系列的事件在正常的伤口愈合中是有益的，允许从 炎性到修复性的巨噬细胞表型需要促进愈合。我们假设在 正常创面愈合的演变及干扰素β介导的创面巨噬细胞SETDB2的诱导 抑制NFKB介导的炎症和代谢基因导致创面减少 发炎和加强伤口修复。我们进一步假设，这一过程不会发生在 糖尿病创面没有在创面巨噬细胞中诱导SETDB2时，导致 发炎和无法愈合的伤口。这一假设将通过以下具体目标进行调查： 1)阐明SETDB2对正常和糖尿病创面中NFkB介导的基因表达的调节 巨噬细胞；2)确定干扰素β介导的上调巨噬细胞特异性SETDB2的机制(S) 在正常和糖尿病创面组织中的表达；以及3)确定SETDB2调节的尿酸在 正常和糖尿病伤口愈合过程中的巨噬细胞表型。

PROJECT SUMMARY/ABSTRACT Non-healing wounds in patients with Type 2 Diabetes (T2D) are a major cause of morbidity and mortality and are increasing at an alarming rate. The factors controlling macrophage function and how these cells transition from an inflammatory to a reparative phenotype in wound tissues are not understood; leaving a large deficit in our ability to prevent and treat these wounds. Our laboratory is investigating novel epigenetic changes, induced via post-transitional modifications of histones, as mechanism(s) to regulate the macrophage phenotype during wound healing. We present data that the cytokine environment established in wounds following injury induces the expression of specific epigenetic machinery in macrophages that control gene transcription, and hence, function. Using human cells and our experimental murine model of wound healing, we have identified that interferon-beta (IFNβ) induces the expression of SETDB2, an epigenetic-based lysine methyltransferase that is responsible for setting a suppressive histone mark that results in the silencing of inflammatory and metabolic genes. This sequence of events is beneficial in normal wound healing, allowing for the transition from an inflammatory to a reparative macrophage phenotype needed to promote healing. We hypothesize that during the evolution of normal wound healing, IFNβ-mediated induction of SETDB2 in wound macrophages represses NFKB-mediated inflammatory and metabolic genes resulting in decreased wound inflammation and enhanced wound repair. We further postulate that this process does not occur in diabetic wounds where SETDB2 is not induced in wound macrophages, resulting in increased inflammation and non-healing wounds. This hypothesis will be investigated via the following specific aims: 1) Elucidate the regulation of NFkB-mediated gene expression by SETDB2 in normal and diabetic wound macrophages; 2) Determine the IFNβ-mediated mechanism(s) that upregulate macrophage-specific SETDB2 expression in normal and diabetic wound tissue; and 3) Establish the role of SETDB2-regulated uric acid on normal and diabetic wound macrophage phenotypes during healing.